During the previous grant period, the investigators reported the isolation and characterization of a panel of islet-reactive T-cell clones that protect NOD mice from development of insulitis and diabetes. In contrast to the panel of islet-reactive T-cell clones isolated by Dr. Kathryn Haskins, the investigators' panel of islet-reactive T-cell clones do not exacerbate disease in NOD recipient mice; instead, they suppress development of IDDM. The tow panels of T-cell clones are similar in that they both express CD4 and produce Th1 profiles of cytokines. Other laboratories have also reported isolation of autoreactive T-cell clones capable of inhibiting IDDM development in NOD mice. It remains puzzling as to how some autoreactive T-cells will develop pathogenic effector function, while others develop protective effector function. The investigators have reported that the protective capacity of their panel of islet-reactive T-cell clones correlated with production of an activity, MLR-IA, that potently inhibits allo-MLR. They showed that the partially purified MLR-IA protein inhibited adoptive transfer of IDDM in NOD mice. They have characterized the biological characteristics of this activity in detail. Their study revealed that MLR-IA is a protein that suppresses T-cell proliferation, stimulates IL-4 production, inhibits IFN-g production, and which is distinct from other known cytokines. Their data strongly suggest that MLR-IA plays a major role in the protective action of NOD-5 T-cells from being autoaggressive, and 3) to determine whether the NOD-5 T-cell receptor specificity promotes development of the protective phenotype. The investigators believe tat their proposed study should have implication for development of an immunoregulatory cytokine, MLR-IA, for prevention and therapy of IDDM. Studies directed at delineating elements that promote development of protective T effector functions could point to new strategies for therapeutic intervention.